Novel trifluoromethyl-quinolines

ABSTRACT

7- OR 8-TRIFLUOROMETHYL-QUINOLINES OF THE FORMULA   WHEREIN N IS 1 OR 2 AND R is selected from the group consisting of saturated and unsaturated heterocyclic having an oxygen atom, a nitrogen atom or both a nitrogen and oxygen atom and their non-toxic, pharmaceutically acceptable acid addition salts having analgesic and anti-inflammatory activity and their preparation.

United States Patent Allais et al.

NOVEL TRIFLUOROMETHYL-QUINOLINES Inventors: Andre Allais, Les Lilas; Jean Meier,

Coeuilly-Champigny, both of 'France Roussel-UCLAF, Paris, France The portion of the term of this patent subsequent to June l0, 1986, has been disclaimed.

Filed: June 3, 1969 Appl. No.: 830,148

Foreign Application Priority Data Nov. 8, 1968 France 173.099

Assignee:

Notice:

US. Cl. 260/287 R; 260/247.2 B; 424/258 Int. Cl. C07D 215/14 Field of Search 260/287, 247.2

[56] References Cited UNITED STATES PATENTS 9/1964 Allais et a1 260/287 3/1965 Allais et al.. 260/287 6/1969 Allais et al.... 260/287 8/1969 Allais et a1 260/287 *Oct. 7, 1975 Primary ExaminerDonald G. Daus Assistant Examiner.lames H. Turnipseed Attorney, Agent, or Firm-Hammond & Littell [5 7] ABSTRACT 7- or 8-trifluoromethyl-quinolines of the formula sic and anti-inflammatory activity and their preparation.

4 Claims, No Drawings NOVEL TRIFLUORONIETHYL-QUINOLINES OBJECTS OF THE INVENTION It is an object of the invention to provide the novel quinolines of formula 1 and their acid addition salts.

It is another object of the invention to provide a novel process for the preparation of the quinolines of formula I.

It is a further object of the invention to provide novel analgesic and anti-inflammatory compositions.

It is an additional object of the invention to provide a novel method of treating pain and inflammation in warm-blooded animals.

These and other objects and advantages of the invention will become obvious from the following detailed description.

THE INVENTION The novel compounds of the invention are selected from the group consisting of 7- and 8-trifluoromethylquinolines of the formula wherein n is l or 2 and R is selected from the group consisting of unsaturated and saturated heterocyclics having a hetero-oxygen, a hetero-nitrogen and a hetero-nitrogen and oxygen, and their non-toxic, pharmaceutically acceptable acid addition salts. Among the more interesting compounds of formula I are 4-[2'-(,B- pyridyl-methoxycarbonyl )]-phenylamino-7-trifluoromethyl-quinoline, 4- 2 a-tetrahydrofurfuryloxycarbonyl)]-phenylamino-7-trifluoromethyl-quinoline, and 4-[2'-(B- morpholinoethoxycarbonyl)]-phenylamino-7-trifluoromethyl-quinoline.

The novel compounds of formula I and their acid addition salts possess remarkable anti-inflammatory and analgesic activity. They are useful for the treatment of rheumatic and arthritic complaints and inflammation of the circulatory system.

Examples of suitable heterocyclic radicals falling within the definition of R are particularly 5- and 6- member hetero groups such as pyridyl, tetrahydrofuryl, morpholino, pyrrolidinyl, oxazolyl, etc.

Examples of suitable acids for the non-toxic, pharmaceutically acceptable acid addition salts are inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. and organic acids such as acetic acid, tartaric acid, citric acid, maleic acid, malonic acid, fumaric acid, etc.

The novel process of the invention for the preparation of the 7- or 8-trifluoromethyl-quinolines of formula 1 comprises reacting a 4-(2-alkoxycarbonyl)- phenylamino-7- or 8-trifluoromethyl-quinoline of the formula 1 B COOR wherein R is lower alkyl of 1 to 7 carbon atoms with an alcohol of the formula HO (CH R 111 wherein n and R have the above definitions in the presence of a strong alkaline agent to form the desired compound of formula I which may be reacted with an acid to form the corresponding acid addition salt.

In preferred embodiments of the process, R is methyl and the alcohol of formula III is derived from tetrahydrofuran, pyridine or morpholine. The alkaline agent is preferably an alkali metal, an alkali metal amide or an alkali metal hydride.

The 4-(2-alkyloxycarbonyl)-phenylamino-7- or 8-) trifluoromethyl-quinolines of formula 11 can be prepared by the process of Belgian Pat. No. 710,321 or French Pat. No. 1,369,967 by condensation of a suitably substituted 4-chloro-quino1ine and an alkyl anthranilate. An example of such a preparation, resulting in 4-( 2 -methoxycarbonyl )-phenylamino-8-trifluoromethyl-quinoline, is given in Example I, by way of illustration. It is worthwhile to note that this compound also possesses an important anti-inflammatory activity and intense analgesic activity.

The anti-inflammatory and analgesic compositions of the invention are comprised of at least one compound of formula I or its acid addition salt and a major amount of a pharmaceutical carrier. The compositions may be in the form of injectable solutions or suspensions, in ainpoules or multidose flacons, or in the form of tablets, coated tablets, capsules, syrups, suppositories and ointments.

The novel method of treating pain and inflammations in warm-blooded animals comprises administering to warm-blooded animals a safe and effective amount of at least one compound of formula I or its non-toxic, pharmaceutically acceptable acid addition salts. The said compounds may be administered orally, perlingually, transcutaneously, rectally or topically on skin or mucous membranes. The usual useful daily dose is 0.9 to 50 mg/kg depending upon the method of administration.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE I Preparation of 4-( 2 -methoxycarbonyl )-pheny1amino- S-trifluoromethyl-quino1ine Step A: Ethyl o-trifluoromethylanilinomethylene malonate A mixture of 54.8 g. of o-trifluoromethylaniline and 73.5 g. of ethyl ethoxymethylene malonate was heated to 120C. under an inert atmosphere and held at this temperature for one hour while eliminating the ethanol thus formed by distillation. The mixture was cooled and the elimination of the ethanol was completed by distilling under reduced pressure. After cooling, 115 g. of ethyl o-trifluoromethylanilinomethylene malonate, used as is for the following stage, was obtained. A sample of this product recrystallized from petroleum ether (boiling point 65 to 75C.) had a melting point of 94C.

Analysis: C H F NO molecular weight 331.288. Calculated: C, 54.38%; H, 4.87%; F, 17.21%; N, 4.23%. Found: C, 54.5%; H, 4.7%; F, 16.8%; N, 4.5%.

Step B: 3-carbethoxy-4-hydroxy-8-trifluoromethyl-quinoline A mixture of 113 g. of crude ethyl otrifluoromethylanilinomethylene malonate, obtained in Step A, and 1 15 cc of diphenyl ether was heated rapidly under an inert atmosphere. At about 195C, the ethanol formed began to distill off. At the end of about 30 minutes, the internal temperature reached 250C. and the reaction mixture was heated to reflux and maintained at reflux for one hour. After cooling, 25 cc of acetone were added to the reaction mixture which was allowed to stand to crystallize. The crystals thus formed were recovered by suction-filtering and washed and dried to obtain 71.5 g. of 3-carbethoxy-4-hydroxy- 8 trifluoromethyl-quinoline with a melting point of 210 to 214C., which was used as is for the following step. A sample of this product upon recrystallization from ethanol had a melting point of 216C.

Analysis: C,;,H ,F;,NO molecular weight 285.218. Calculated: C, 54.74%; H, 3.53%; F, 19.98%; N, 4.91%; Found: C, 54.5%; H, 3.8%; F, 19.6%; N, 4.9%.

Step C: 3-carboxy-4hydroxy-8-trifluoromethyl-quinoline 70 g. of crude 3-carbethoxy-4-hydroxy-8-trifluoromethyl-quinoline, obtained in Step B, were added to a mixture of 300 cc of water and 100 cc of an aqueous N sodium hydroxide solution under an inert atmosphere. The reaction mixture was heated to reflux and maintained there for two hours and 45 minutes. The solution thus obtained was poured into a mixture of water, ice and 100 cc of an aqueous l 1.8 N hydrochloric acid solution. The precipitate thus fomied was isolated by suction-filtering and washed with water and introduced into a solution of 20 g. of sodium bicarbonate in 2 liters of water. The mixture was heated to 90C. A persistant slightly insoluble substance was removed by filtration. The filtrate was made acidic with acetic acid to adjust the pH to about 5.5. The precipitate thus formed was isolated by suction-filtering and washed and dried to obtain 58 g. of 3-carboxy-4-hydroxy-8-trifluoromethyl-quinoline with a melting point of 290 to 292C, which was used is for the following step. A sample of this product when crystallized from hot and cold acetone with treatment with charcoal gave pure 3-carboxy-4-hydroxy-8-trifluoromethyl-quinoline with a melting point of 292C.

Analysis: C H F NO molecular weight 257.166. Calculated: C, 51.37%. H, 2.35%; F, 22.16%; N, 5.45%. Found: C, 51.6%; H, 2.6%; F, 21.8%; N, 5.3%.

Step D: 4-hydroxy-S-trifluoromethyl-quinoline 56.5 g. of c1 ude 3-carboxy-4-hydroxy-8trifluoromethylquinoline, obtained in Step C, was added to l 10 cc of diphenyl ether under an inert atmosphere. The reaction mixture was rapidly heated to reflux and maintained at reflux for 1 hour and minutes. The reaction mixture was cooled to about 50C. and cc of isopropyl ether were added thereto. The mixture was cooled to 20C. and left to crystallize. The precipitate thus formed was recovered by suction-filtering and washed and dried to obtain 45.8 g. of 4-hydroxy-8-trifluoromethyl-quinoline with a melting point of 180C. A sample of this product was crystallized from acetone with treatment with charcoal to obtain pure 4-hydroxy- 8-trifluoromethyl-quinoline with a melting point of 180C.

Analysis: C H F NO; molecular weight 213.156. Calculated: C, 56.34%; H, 2.84%; F, 26.74%; N, 6.57%. Found: C, 56.6%; H, 3.1%; F, 26.5%; N, 6.5%.

Step E: 4-chloro-8-trifluoromethyl-quinoline Into 130 cc of phosphorus oxychloride, there were introduced in small amounts 44.3 g. of crude 4- hydroxy-8-trifluoromethyl-quinoline, obtained in Step D, and the mixture was left for fifteen minutes at ambient temperature and then heated to reflux and maintained at reflux for one hour. The mixture was cooled and excess phosphorus oxychloride was removed by distillation under reduced pressure. Water, ice, then 80 cc of a 22 Be aqueous solution of ammonia were added to the residue and the mixture was stirred. The aqueous phase was extracted with ether, and the ethereal extracts were washed with a dilute aqueous solution of ammonia, and then with water. After drying, the solution was treated withchareoal and concentrated to dryness to obtain 45.4 g. of 4-chloro-8-trifluoromethylquinoline with a melting point of 78C., which was used as is for the preparation of 4-(2-methoxycarbonylphenylamino)-8-trifluoromethyl-quinoline. A sample of crude 4-chloro-8-trifluorornethyl-quinoline was crystallized from petroleum ether (boiling point to C.) to obtain a product with a melting point of 78C.

Analysis: C H F ClN; molecular weight 231.605. Calculated: C, 51.86%; H, 2.18%; F, 24.61%; C., 15.3%; N, 6.05%. Found: C, 52.2%; H, 2.3%; F, 24.9%; C1, 15.5%; N, 5.8%.

Step F: 4-( 2 '-methoxycarbonyl )-phenylamino-8-trifluoromethyl-quinoline 23. 15 g. of crude 4-chloro-8-trifluoromethylquinoline, obtained in Step E, were added to cc of an aqueous 2N hydrochloric acid solution, followed by the addition of 15.85 g. of methyl anthranilate. The reaction mixture was heated to reflux and held there for fifty minutes. The mixture was cooled and crystallization was allowed to develop. The precipitate thus formed was recovered by suction filtering, and was added to 300 cc of a saturated aqueous solution of sodium bicarbonate. The mixture was agitated and methylene chloride was added and agitation continued. A persistant insoluble substance was removed by filtering and the organic phase was separated by decanting. The latter was washed with water and concentrated to dryness. The residue was crystallized from methanol to obtain 21 .3 g. of 4-( 2'-methoxycarbonyl)-phenylamino-8- trifluoromethyl-quinoline with a melting point of Analysis: C H F N omolecular weight 346.30. Calculated: C, 62.43%; H, 3.78%; F, 16.46%; N, 8.09%. Found: C, 62.2%: H, 4.0%; F, 16.3%; N, 8.0%.

I.R. Spectrum (chloroform) Absorption at 3,297 and 3,264 corresponding to the NH grouping i Absorption at 1,691 corresponding to carbonyl Absorption at 1,142 and 1,147 corresponding to the CF,; grouping.

EXAMPLE I1 4-[ 2 oz-tetrahydrofurfuryloxycarbonyl phenylamino-7-trifluoromethyl-quinoline 40 g. of tetrahydrofurfuryl alcohol and 40 cc of toluene were admixed and water was removed by azeotropic distillation. Then 40 cc of toluene were added and again the mixture was distilled at ordinary pressure and then under a vacuum of mm of mercury. The temperature was adjusted to 85C. and 250 mg of a 50% suspension of sodium hydride in paraffin oil, then 10 g. of 4-(2'-methoxycarbonyl)-phenylamino-7-trifluoromethyl-quinoline (obtained according to the process described in French Pat. No. 1,369,967) were added. The solution stood for 5 hours in vacuo at 85C.

and then was cooled. 100 cc of water were added thereto and the mixture was extracted with ether. The

organic phases were washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness. A mixture of 5 cc of methanol and 5 cc of isopropyl ether were added to the oily residue and the mixture was agitated for 1 hour in a bath of ice and suction-filtered. The precipitate was washed with petroleum ether to obtain 6.8 g. of a crude tetrahydrofurfuryl compound which was recrystallized from hot and cold isopropyl ether to obtain 2.7 g. of 4-(2- tetrahydrofurfuryloxycarbonyl )-phenylamino-7-trifluoromethyl-quinoline. By concentration of the mother liquors from the crystallization, a second yield of 1.8 g. of the compound was obtained making a total of 4.5 g. (Yield: 37%).

4-[ 2'-( a-tetrahydrofurfuryloxycarbonyl phenylamino-7-trifluoromethyl-quinoline appeared in the form of a colorless solid product soluble in alcohol, chloroform, ether and benzene and insoluble in water. lts melting point determined on a Maquenne block was 80C.

Analysis: C H, N O F molecular weight 416.39 Calculated: C, 62.02%; H, 4.98%; N, 9.43%; F, 12.8%; Found: C, 62.2%; H, 5.0%; N, 9.7%; F, 12.4%.

As far as is known, this compound is not described in the literature.

EXAMPLE m 4- 2 ,B-pyridyl-methoxycarbonyl ]-phenylamino-7- trifluoromethyl-quinoline Using the same conditions of Example 11, 45 g. of 3-hydroxymethyl-pyridine and l0 7 g. of 4-(2'- methoxycarbonyl )-phenylamino-7-trifluoromethylquinoline were reacted to obtain 6.2 g. of 4- [2-( 8- pyridyl-methoxycarbonyl ]-phenylamino-7-trifluoromethyl-quinoline.

This product appeared in the form of a pale yellow solid product soluble in alcohol, chloroform and ether and insoluble in water. lts melting point, determined on a Kofler block, was 1 17C.

Analysis: C. -,H ,N O- F,-;; molecular weight 423.38 Calculated: C, 65.26%; H, 3.80%; N, 9.92%; F, 13.46%. Found: C, 65.5%; H, 4.1%; N, 9.7%; F, 13.3%.

As far as is known, this compound is not described in the literature.

EXAMPLE IV 4- 2-( ,B-morpholinoethoxycarbonyl )]-phenylamino-7- trifluoromethyl-quinoline Using the same conditions of Example 11, 43 g. of N-(B-hydroxyethyl)-morpholine and 10 g. of 4-(2'- methoxycarbonyl )-phenylamino-7-trifluoromethylquinoline were reacted to obtain 8.49 g. of 4-[2'-(B- morpholinoethoxycarbonyl ]-phenylamino-7-trifluoromethyl-quinoline.

This product appeared in the form of a pale yellow solid product soluble in alcohol, ether, acetone and chloroform and insoluble in water. lts melting point determined on a Kofler block was C.

Analysis: C23H22N303F3; molecular weight 445.43 Calculated: C, 62.0%; H, 4.98%; N, 9.43%; F, 12.8%; Found: C, 62.2%; H, 5.0%; N, 9.7%; F, 12.4%.

l.R. Spectrum Absorption at 2,780 and 2,850 -Nype As far as is known, this compound is not described in the literature.

EXAMPLE V 4- 2 B-pyridyl-methoxycarbonyl ]-phenylamino-8- trifluoromethyl-quinoline Using the same conditions as in Example 11, 45 gpof 3-hydroxymethyl-pyridine and 10 g. of 4-(2- methoxycarbonyl )-phenylamino-8-trifl uoromethylquinoline were reacted to obtain 6.4 g. of 4-[2'-(B- pyridyl-methoxycarbonyl ]-phenylamino-8-trifluoromethyl-quinoline with a melting pointof C.

Analysis: C H N O F molecular weight 423.38. Calculated: C, 65.26%; H, 3.80%; N, 9.92%; F, l3,46%. Found: C, 65.0%; H, 3.8%; N, 9.9%; F, 13.2%.

As far as is known, this compound is not described in the literature.

PHARMACOLOGICAL DATA Analgesic Activity The test employed was based on the fact noted by Koster et 211. (Fed. Proc. 1959, 18, 412) according to which the intraperitoneal injection of acetic acid provoked repeated characteristic movements of stretching and twisting persisting in mice for more than 6 hours. Analgesics prevent or suppress this syndrome which is an exterior manifestation of a diffuse abdominal pain.

A solution of 6 parts per thousand of acetic acid in water containing 10% of arabic gum was employed and the dose provoking the syndrome in mice under these conditions was 0.01 cc/gm, being 60 mg/kg of acetic acid. The analgesics were administered orally to groups of five mice, which had not been fed for 24 hours, a half hour before the intraperitoneal injection of the acetic acid. The stretchings were observed, noted and counted for each mouse and then additionated by groups of five, during a period of observation of 15 minutes immediately after the injection of acetic acid. The average number of stretchings observed on the 12 control groups of five mice during the period of observation indicated, was established.

The products of the invention which were administered in the form of an aqueous suspension diminished the number of stretchings in a fashion obviously proportional to the doses utilized, as is shown in Table I which compares the products with aspirin.

TABLE 1 Dose of Stretch- Administered ings compared Product in mg/kg to Controls 4-( 2 -tetrahydrofurfuryl- 5 57 oxycarbonyl )-phenylamino- 7 trifluoromethylquin- 10 62 oline 4-[2'-(Bpyridyl- 5 6O methoxycarhonyl phenylamino-7-trifluoro l() 58 methyl-quinoline 4-[ 2'-( fi-morpholino- 5 59 ethoxycarhonl y phenylamino-7-tri I 45 fluoromethyl-quino line 20 14 Table I shows that the 50% active dose (AD for the compounds of the invention lies between 10 and 15 mg/kg compared to an AD of 160 mg/kg for aspirin.

Anti-inflammatory Activity The anti-inflammatory activity of the following compounds was determined by the method of Branceni et al. slightly modified (Arch. Int. Pharmacodyn, Vol. 152, 1964, p. 15). The test used consisted in administering in a single injection 1 mg of naphtoylheparamine under the aponevrosis of the sole of a hind paw of rats weighing 150 gm. (This injection being destined to provoke the formation of an inflammatory edema). The products to be studied were administered in aqueous suspension by oral route one hour before the injection. The amount of inflammation was determined by plethysmometry, the volume of the paw being measured immediately prior and 2 hours after the irritating injection. The volumes at the hour H were adjusted to their initial level, by the analysis of covariance. The degree of inflammation is calculated as a percentage of that of the controls animals. The results are summarized in Tables llu, 11b and 110.

TABLE [la 4-[2'-(u-tetrahydrofurfuryloxycarbonyl)lphenylamino-7-trifluoromethyl-quinolinc Volume at Dose 2 hrs. ad- Adminijusted by stered lnitial Covariance of [nin mg/kg Volume Analysis flammation Controls 0 56.8 100 Treated 48.8 67

Controls 0 54.8 100 Treated 5 46.9 68

TABLE 11b 4-[2'-(B-pyridyl-methoxycarbonyl)]-phenylamino-7-trifl uoromethyl-quinoline Volume at Dose 2 hrs. ad- Adminijusted by stered Initial Covariance A of inin mg/kg Volume Analysis flammation Controls 0 54.8

30.03 Treated 10 45.2 61 30 33.9 15 Controls 0 52.0 100 31.0 Treated 5 48.1 81

TABLE I10 4- [2 -(B-morph0linoethoxycarbonyl)]-phenylamino-7-trifluoromethyl-quinoline Volume at Dose 2 hrs. ad- Adminijusted by stered Initial Covariance '71 of lm in mg/kg Volume Analysis flammation Controls 0 57.3 100 30.8 Treated 5 50.3 74 15 45.8 57 45 36.4 21

This test shows that the products of the invention have an important anti-inflammatory activity as their AD is between 10 and 15 mg/kg as compared to an AD of 30 to 60 mg/kg for aspirin under the same test conditions.

Various modifications of the compositions and method of the invention may be made without departing from the spirit or scope thereof.

We claim:

1. A compound selected from the group consisting of 7- and 8-trifluoromethyl-quinolines of the formula OO-( CH -R CF V cally acceptable acid addition salts.

4. A compound of claim 1 selected from the group consisting of 4-[2-B-pyridyl-methoxycarbonyl phenylamino-8-trifluoromethyl-quinoline and its nontoxic, pharmaceutically acceptable acid addition salts. l l 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 7-AND 8-TRIFLUOROMETHYL-QUINOLINES OF THE FORMULA
 2. A compound of claim 1 selected from the group consisting of 4-(2''-( Beta -pyridyl-methoxycarbonyl))-phenylamino-7-trifluoromethyl-quinoline and its non-toxic, pharmaceutically acceptable acid addition salts.
 3. A compound of claim 1 selected from the group consisting of 4-(2''-( Alpha -tetrahydrofurfuryloxycarbonyl))-phenylamino-7-trifluoromethyl-quinoline and its non-toxic, pharmaceutically acceptable acid addition salts.
 4. A compound of claim 1 selected from the group consisting of 4-(2''- Beta -pyridyl-methoxycarbonyl))-phenylamino-8-trifluoromethyl-quinoline and its non-toxic, pharmaceutically acceptable acid addition salts. 